U.S. patent number 6,582,711 [Application Number 08/781,095] was granted by the patent office on 2003-06-24 for hydroalcoholic compositions thickened using polymers.
This patent grant is currently assigned to 3M Innovative Properties Company. Invention is credited to Robert A. Asmus, Matthew T. Scholz.
United States Patent |
6,582,711 |
Asmus , et al. |
June 24, 2003 |
**Please see images for:
( Certificate of Correction ) ** |
Hydroalcoholic compositions thickened using polymers
Abstract
An antimicrobial hydroalcoholic composition comprising
hydroalcoholic solvent system comprising a lower alcohol and water
in a weight ratio of at least about 50:50; a thickener system
comprising at least one cationic or nonionic polymeric thickener
that is solid at ambient temperature; and a secondary antimicrobial
agent.
Inventors: |
Asmus; Robert A. (Hudson,
WI), Scholz; Matthew T. (Woodbury, MN) |
Assignee: |
3M Innovative Properties
Company (St. Paul, MN)
|
Family
ID: |
25121681 |
Appl.
No.: |
08/781,095 |
Filed: |
January 9, 1997 |
Current U.S.
Class: |
424/405;
523/122 |
Current CPC
Class: |
A61P
17/00 (20180101); A01N 31/02 (20130101); A61K
31/155 (20130101); A61P 31/00 (20180101); A01N
31/02 (20130101); A01N 47/44 (20130101); A01N
25/10 (20130101); A01N 31/02 (20130101); A01N
2300/00 (20130101) |
Current International
Class: |
A01N
31/02 (20060101); A01N 31/00 (20060101); A01N
025/02 (); A61K 009/08 (); A61K 009/10 (); A61K
047/32 () |
Field of
Search: |
;424/78.02,484,486,487,405 ;523/122 ;514/944 |
References Cited
[Referenced By]
U.S. Patent Documents
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|
Primary Examiner: Webman; Edward J.
Attorney, Agent or Firm: Lambert; Nancy M.
Claims
What is claimed is:
1. An antimicrobial hydroalcoholic composition comprising: (a) a
hydroalcoholic solvent system comprising a lower alcohol selected
from the group consisting of ethanol, 2-propanol, n-propanol, and
combinations thereof, and water in a weight ratio of lower alcohol
to water of at least about 60:40; (b) a thickener system comprising
at least one cationic polymeric thickener derived from
ethylenically unsaturated monomers that is solid at ambient
temperature; wherein the cationic thickener is selected such that
the composition has a viscosity of at least about 10,000 centipoise
at 23.degree. C.; wherein the thickener system is present in an
amount of at least about 0.5% by weight, based on the total weight
of the composition; and
a secondary antimicrobial agent.
2. The composition of claim 1 which has a pH of at least about
5.
3. The composition of claim 1 wherein the secondary antimicrobial
agent comprises a chlorhexidine salt in an amount of at least about
0.5% by weight, based on the total weight of the composition, and
the composition has a viscosity of greater than about 60,000 cps at
23.degree. C.
4. The composition of claim 1 wherein the ethylenically unsaturated
monomers are selected from the group of acrylates, acrylamides,
vinyl lactams, vinyl acetates, methyl vinyl ethers, styrene, and
acrylonitrile.
5. The composition of claim 1 wherein the thickener system further
comprises at least one nonionic polymeric thickener.
6. The composition of claim 5 wherein the nonionic polymeric
thickener is selected from the group consisting of modified
celluloses, associative polymers derived from nonionic
ethylenically unsaturated monomers wherein at least one comonomer
has at least 16 carbon atoms, and polymers based on ethylenically
unsaturated monomers selected from the group of acrylates,
acrylamides, vinyl lactams, vinyl acetate and it hydrolyzed
derivatives, methyl vinyl ethers, styrene, and acrylonitrile.
7. The composition of claim 1 wherein the cationic polymer is a
synthetic poly(quaternary amine) polymer.
8. The composition of claim 1 wherein the thickener system is
selected such that the composition has a viscosity of at least
about 50,000 centipoise at 23.degree. C.
9. The composition of claim 1 wherein the thickener system is
present in an amount of less than about 10% by weight, based on the
total weight of the composition.
10. The composition of claim 1 wherein the thickener system is
present in an amount of greater than about 2% by weight, based on
the total weight of the composition.
11. The composition of claim 1 wherein the composition is
substantially free of ions in excess of the cations and counterions
associated with the cation polymer.
12. The composition of claim 1 wherein the polymer is at least
partially crosslinked.
13. The composition of claim 12 wherein the partially crosslinked
polymer comprises an N-vinyl lactam.
14. The composition of claim 1 wherein the secondary antimicrobial
agent is selected from the group consisting of chlorhexidine salts,
iodine, triclosan, PCMX, and mixtures thereof.
15. The composition of claim 1 wherein the cationic polymeric
thickener is soluble.
16. The composition of claim 1 wherein the cationic polymeric
thickener is swellable.
17. The composition of claim 1 wherein the cationic polymeric
thickener is an associative polymeric thickener.
18. The composition of claim 17 wherein the associative polymeric
thickener is derived from ethylenically unsaturated monomers
wherein at least one comonomer has an alkyl side chain of at least
16 carbon atoms.
19. The composition of claim 1 further comprising at least one
lipophilic emollient.
20. The composition of claim 1 wherein the lower alcohol is
selected from the group consisting of ethanol, 2-propanol,
n-propanol, and mixtures thereof.
21. The composition of claim 1 which is stable and does not
separate more than about 10% by volume when centrifuged for 30
minutes at 1545.times.g.
22. The composition of claim 1 further comprising a pharmaceutical
agent selected from the group consisting of steroidal
antiinflammatory drugs; nonsteroidal antiinflammatory drugs;
penicillins; cephalosporins; quinolones; antiprotazoals;
antifungals; vasodilators; calcium channel blockers;
bronchodilators; enzyme inhibitors; antihypertensives; leukotriene
antagonists; antiulceratives; steroidal hormones; antivirals;
immunomodulators; local anesthetics; cardiotonics; antitussives;
antihistamines; narcotic analgesics; peptide hormones; cardioactive
products; proteinaceous products; enzymes; antinauseants;
anticonvulsants; immunosuppressives; psychotherapeutics; sedatives;
anticoagulants; analgesics; antimigraine agents; antiarrhythmic
agents; antemetics; anticancer agents; neurologic agents;
hemostatics; antiobesity agents pharmaceutically acceptable salts
and esters thereof; nicotine; and combinations thereof.
23. The composition of claim 1 wherein the ethylenically
unsaturated monomers are selected from the group of acrylates and
acrylamides.
24. The composition of claim 23 wherein the ethylenically
unsaturated monomer further comprises a nonionic monomer selected
from the group of acrylates, acrylamides, vinyl lactams, vinyl
acetates, methyl vinyl ethers, styrene, and acrylonitrile.
25. The composition of claim 22 wherein the enzyme inhibitor is
selected from the group consisting of collagenase inhibitors,
protease inhibitors, elastase inhibitors, lipoxygenase inhibitors,
and angiotensin converting enzyme inhibitors.
Description
FIELD OF THE INVENTION
The present invention relates to compositions useful as surgical
hand preparations and antimicrobial hand lotions. More specifically
the invention relates to stable hydroalcoholic compositions
thickened using nonionic or cationic polymers.
BACKGROUND OF THE INVENTION
Control of nosocomial infection and exposure to infectious disease
is of paramount concern to doctors, nurses, and clinicians who work
in hospitals and surgery centers. One of the most effective methods
for controlling infection is regimented hand disinfection before
and possibly after each patient contact and particularly before and
after each surgical procedure. Hand disinfection is generally
accomplished using antimicrobial soaps with water. These soaps are
usually formulated to include either povidone-iodine (usually 7.5%
by weight) or chlorhexidine digluconate (CHG) (usually 2% or 4% by
weight) as the active antimicrobial agent. In addition, these
formulated soaps may contain surfactants and possibly low levels of
humectants such as glycerin.
Hand disinfection is also accomplished using presurgical scrub
replacements. These are used instead of the soap and water scrub.
Presurgical scrub replacements ideally achieve bacterial kill equal
to or better than a traditional soap and water scrub and in a
shorter period of time. Additionally, they maintain or improve the
skin's natural barrier to microbial and chemical contamination
while providing acceptable tactile properties. Examples of
presurgical scrub replacements include hydroalcoholic gels which
generally include high levels of either ethanol or isopropanol as
the disinfecting agent and also include a thickener and optionally
a humectant (e.g., glycerin).
To date, thickeners used in hydroalcoholic gels have been based
primarily on anionic polymers such as polyacrylic acid (sold under
the tradename "CARBOPOL" by BF Goodrich Specialty Polymers and
Chemicals Division of Cleveland, Ohio). See, for example, U.S. Pat.
No. 4,956,170 (Lee) and U.S. Pat. No. 5,167,950 (Lins). These
compositions are generally incompatible with cationic compounds
such as chlorhexidine gluconate. There are a few reports of
nonionic and cationic polymeric thickeners being used as well. See,
for example, U.S. Pat. No. 4,478,853 (Chausee) and International
Publication No. WO 93/007903 (Deckner). These hydroalcoholic
compositions have relatively low levels of alcohol, generally too
low to provide rapid and effective antimicrobial activity.
U. S. Pat. No. 5,512,199 (Khan) discloses a hydroalcoholic wipe
composition, incorporating nonionic and cationic polymeric
emollients or humectants. These compositions have very low
viscosities, too low to be used as a lotion. U.S. Pat. No. 4,
981,678 (Tomlinson) and U.S. Pat. No. 4,981,698 (Tomlinson) provide
hydroalcoholic biocidal compositions incorporating low molecular
weight polymeric emollients such as polyglycerol and polyvinyl
pyrrolidone. These polymers do not provide adequate thickening in
hydroalcoholic lotions.
In other hydroalcoholic systems, such as those described in U.S.
patent application Ser. Nos. 08/493,714 and 08/493,695 (both of
which were filed on Jun. 22, 1995 and assigned to 3M Company),
nonionic, anionic, cationic, or zwitterionic emulsifiers are used
as thickeners for a wide range of concentrations of alcohol,
without the need for a polymeric thickener such as polyacrylic
acid. Although these systems are highly desirable, other high
viscosity hydroalcoholic compositions useful as an antimicrobial
lotion, for example, are still needed.
SUMMARY OF THE INVENTION
This invention provides compositions useful as products for skin
disinfection such as presurgical hand preparations and lotions that
are easily washed off hands with water, preferably with no apparent
residue. The preferred compositions of this invention, in general,
have a very nice feel after both single and multiple applications.
Preferred compositions maintain or improve the skin condition after
multiple applications with no slimy or abnormal feeling noticed
during post application hand washing. When used as a presurgical
scrub replacement, this invention achieves bacterial, fungal, and
viral kill equal to or better than a traditional soap and water
scrub in a shorter period of time while maintaining or improving
the skin's natural barrier to microbial and chemical contaminants.
Additionally, these compositions are compatible with cationic
additives, such as chlordexidine digluconate. The invention
overcomes the shortcomings of past compositions by providing a
viscous cosmetically elegant lotion that is substantially nontacky
and maintains or improves skin condition and is compatible with
cationic additives. Further, the composition has a cosmetically
elegant feel and may be dispensed as a lotion or as a foam.
One embodiment of the present invention is an antimicrobial
hydroalcoholic composition comprising: a hydroalcoholic solvent
system comprising a lower alcohol and water in a weight ratio of at
least about 50:50; a thickener system comprising at least one
cationic polymeric thickener that is solid at ambient temperature;
wherein the cationic thickener is selected such that the
composition has a viscosity of at least about 10,000 centipoise at
23.degree. C.; wherein the thickener system is present in an amount
of at least about 0.5% by weight, based on the total weight of the
composition; and a secondary antimicrobial agent.
Another embodiment is an antimicrobial hydroalcoholic lotion
comprising: a hydroalcoholic solvent system comprising a lower
alcohol and water in a weight ratio of at least about 60:40; a
thickener system consisting essentially of one or more nonionic
polymeric thickeners, at least one of which is solid at ambient
temperature; wherein the one or more polymeric thickeners are
selected such that the composition has a viscosity of at least
about 4,000 centipoise at 23.degree. C.; and further wherein the
thickener system is present in an amount of at least about 0.5% by
weight, based on the total weight of the composition; and a
secondary antimicrobial agent.
Yet another embodiment of the invention is an antimicrobial
hydroalcoholic lotion comprising: a hydroalcoholic solvent system
comprising a lower alcohol and water in a weight ratio of at least
about 60:40; a thickener system comprising at least one associative
polymeric thickener that is solid at ambient temperature; wherein
the associative polymeric thickener is selected such that the
composition has a viscosity of at least about 4,000 centipoise at
23.degree. C.; wherein the thickener system is present in an amount
of at least about 0.5% by weight, based on the total weight of the
composition; and a secondary antimicrobial agent.
Definitions
"Ambient temperature" as used herein refers to the temperature
range of about 21-25.degree. C.
"Emollient" as used herein refers broadly to materials which are
capable of maintaining or improving the moisture level, compliance,
or appearance of the skin when used repeatedly.
"Emulsifier" as used herein is synonymous with "surfactant" and
refers to molecules comprising hydrophilic (polar) and hydrophobic
(non-polar) regions on the same molecule.
"Emulsion" as used herein refers to a stable dispersion of one
liquid in a second immiscible liquid. Emulsion also refers to
stable dispersions of a solid in an immiscible liquid wherein the
solid was formed by cooling below the freezing point of the solid
composition.
"Lotion" means liquid or cream, free of any propellant.
"Polymer" as used herein refers to a natural, modified-natural, or
synthetic molecule having repetitive units and a number average
molecular weight of at least about 20,000.
"Solvent," "solvent system," or "hydroalcoholic solvent" as used
herein refer to the alcohol and water combination in the present
invention.
"Stable" as used herein refers to a composition that displays less
than or equal to 10% by volume separation after centrifuging at
1545.times.g for 30 minutes at ambient temperature.
"Surfactant" as used herein is synonymous with "emulsifier," the
definition of which is given above.
"Thickener System" as used herein refers to at least one nonionic
or cationic polymer that is solid at ambient temperature.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a graph of viscosity loss as a function of excess ion
concentration.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides a hydroalcoholic composition comprised of a
lower chain alcohol, water, a thickening system, and a secondary
antimicrobial agent (i.e., an antimicrobial agent other than the
lower alcohol). The thickening system includes at least one
nonionic or cationic polymeric thickener (or mixture thereof) that
is solid at ambient temperature. Significantly, the polymeric
thickeners are capable of thickening a hydroalcoholic solvent
system containing a ratio of a lower alcohol to water of about
50:50, and even higher ratios (e.g., 60:40 and above). Such high
concentrations of alcohol are important for providing compositions
that have highly effective antimicrobial activity and are fast
drying.
Furthermore, the compositions of the present invention preferably
have a pH of at least about 5, more preferably at least about 5.5,
and most preferably at least about 6. The pH is preferably no
greater than about 9.5, more preferably no greater than about 8.5,
and most preferably no greater than about 8.
Hydroalcoholic Solvent System
The compositions of the present invention include one or more
alcohols in combination with water, thereby producing a
hydroalcoholic solvent system. The alcohol used in the compositions
of the present invention is a lower chain hydrocarbon alcohol
(referred to herein as a "lower alcohol"), particularly a C1-C4
alcohol (i.e., an alcohol containing 1-4 carbon atoms). In
preferred embodiments, the alcohol is ethanol, 2-propanol (i.e.,
isopropanol), or n-propanol. In more preferred embodiments, the
alcohol is ethanol. Ethanol is a preferred alcohol because it
provides quick killing of a broad spectrum of microbes.
Furthermore, it has an acceptable odor to health care practitioners
and patients.
The lower alcohol to water ratio in the compositions of the present
invention is at least about 50:50 by weight (i.e., the lower
alcohol is present in an amount of at least about 50 weight
percent, and the water is present in an amount of about 50 weight
percent, based only on the weight of the water plus the lower
alcohol within the composition), and preferably at least about
60:40, by weight. Typically, compositions of the present invention
have an alcohol to water ratio of no greater than about 99:1 by
weight. Compositions having an alcohol to water ratio within a
range of about 50:50 to 95:5 by weight (i.e., 50-95 weight percent
alcohol and 5-50 weight percent water, based only on the weight of
water plus lower alcohol in the composition) ensure an efficacious
immediate bacterial kill, particularly when used in combination
with a secondary antimicrobial agent (i.e., an antimicrobial agent
other than the lower alcohol). In particularly preferred
embodiments, the lower alcohol to water ratio is within a range of
about 50:50 to about 85:15, and more preferably about 60:40 to
about 75:25. Higher ratios of alcohol to water are used in
preferred embodiments containing secondary antimicrobial agents for
optimum antimicrobial activity and to ensure the composition is
fast drying.
Thickener System
The thickener system useful in this invention affects the cosmetic
attributes of the final composition. Preferably, hand preps and
lotions of the invention have the following desirable cosmetic
attributes. The composition should not result in excessive clumping
of glove powder beneath powdered surgical gloves and should not
affect the integrity of the glove material. Preferred compositions
when applied to the skin and allowed to dry, do not result in
balling up when rubbed. The compositions should preferably maintain
an acceptable viscosity (e.g., at least about 4000 centipoise) at
ambient temperatures (i.e., 21-25.degree. C.), and preferably up to
about 35.degree. C. Preferred compositions are stable to heat and
cool cycles (heating up to 50.degree. C. or higher and cooling to
ambient temperature) as well as freeze/thaw cycles (cooling to
-30.degree. C. and warming to ambient temperature). All of these
cosmetic attributes are affected by the types and amounts of
polymers chosen.
The thickener system of the invention is compatible with the
hydroalcoholic solvent system described above in order to provide
suitable stability, acceptable cosmetic properties, and appropriate
viscosity. Compositions of this invention have a viscosity of at
least about 4,000 centipoise (cps), preferably at least about
10,000 cps, more preferably at least about 20,000 cps, even more
preferably at least about 50,000 cps, and most preferably at least
about 80,000 cps (and even as high as about 500,000 cps or more),
at 23.degree. C., measured using a very low shear viscometer such
as Brookfield LVDV-I+ viscometer and T spindles with a heliopath
adapter. Because certain optional ingredients, such as emollients,
may effect the viscosity (either positively or negatively), the
measured viscosity is that of the final composition.
The thickener system can be prepared from one or more nonionic or
cationic polymers, preferably both nonionic and cationic polymers.
Each of these may be chosen from a single class of compounds or
from more than one class. Typically, anionic thickeners have been
used to thicken hydroalcoholic solvent systems. It was unexpected
that nonionic and cationic polymers could also thicken
hydroalcoholic solvent systems, particularly those containing high
levels of alcohol.
Significantly, thickener systems of the present invention are
capable of achieving high viscosities at relatively low total
polymer concentrations. The total concentration of nonionic or
cationic polymers (or both) present in the thickener system is
preferably less than about 10% by weight, more preferably less than
about 8% by weight, and most preferably less than about 6% by
weight, of the total composition of the present invention.
Preferably, the total concentration of the polymeric thickener
system can be as little as about 0.5% by weight, based on the total
weight of the composition. For certain embodiments, however, the
total concentration of thickener system is greater than about 2% by
weight, based on the total weight of the composition.
As used herein, a polymeric thickener is considered part of the
thickener system if it is nonionic or cationic and its presence in
the composition results in an increase in the viscosity of the
composition. Certain polymers that do not have these
characteristics may also be present in the composition but do not
contribute significantly to the viscosity of the composition. For
purposes of this invention, they are not considered part of the
thickener system. For example, certain nonionic polymers such as
lower molecular weight polyethylene glycols (e.g., those having a
molecular weight of less than about 20,000) do not increase the
viscosity of the composition significantly. These are considered an
emollient or humectant, for example, rather than part of the
thickener system.
The cationic polymers of this invention are selected from both
permanently charged quaternary polymers (those polymers comprising
quaternary amines such Polyquaternium 4, 10, 24, 32, and 37
described below) as well as protonated primary, secondary and
tertiary amine functional polymers which have been protonated with
a suitable protonic acid. Preferred protonated cationic polymers
are based on tertiary amines. The protonated cationic polymers are
preferably protonated with suitable acids that will not result in
undue skin irritation such as C1-C10 alkylcarboxylic acids
optionally substituted by oxygen (e.g., acetic acid, alpha
hydroxyacids such as lactic acid, gluconic acid, and the like),
C1-C10 alkylsulfonic acids (e.g., methylsulfonic acid and
ethylsulfonic acid), C1-C10 alkylhydrogensulfates (e.g.,
methylhydrogensulfate) and mineral acids (e.g., hydrochloric acid,
hydrobromic acid, sulfuric acid, and phosphoric acid and the like).
The charge on protonated cationic polymers is pH dependent. For
this reason, in order to ensure the polymer is sufficiently
protonated, the pH must be adjusted appropriately and should be in
the range of 5-9.5, preferably 6-8, and most preferably 6.5-7.5. It
should be noted that it is not necessary to have all of the amines
on a particular polymer protonated. The level of protonation will
to a certain extent be pH dependent. With certain polymers in order
to obtain optimum thickening with low skin irriation it may be
beneficial to only protonate a small percentage of the available
amine groups while with other polymers it may be beneficial to
protonate substantially all of the amine groups. This will be
easily determined by one skilled in the art. The quaternary,
tertiary, secondary and primary amine functional polymers may be
chosen from natural polymers, modified natural polymers as well as
synthetic polymers. These polymers may be soluble or swellable in
the hydroalcoholic solvent. Furthermore, these polymers may also
possess hydrophobic side chains and thus be associative
polymers.
In the compositions of the present invention, at least one of the
polymeric thickeners in a pure state is a solid at ambient
temperature. In preferred embodiments, all of the polymeric
thickeners are solid at ambient temperature. Such solid polymers
typically are those having a relatively high glass transition
temperature (Tg). Preferably, solid polymers have a Tg of at least
about 25.degree. C., more preferably at least about 50.degree. C.,
and most preferably at least about 80.degree. C. Preferably, the
solid polymeric thickeners are selected such that the composition
has a viscosity of at least about 4,000 centipoise at 23.degree.
C.
Preferred thickener systems used in the compositions of the present
invention are capable of producing viscoelastic compositions that
are very stable. By varying the amount and type of polymer, the
degree of elasticity can be adjusted from almost a purely viscous
composition to a highly elastic and even gel-like composition. If
emollients are added, increasing the elasticity and/or yield stress
of the system imparts added stability to prevent separation of
immiscible emollients. Excessive elasticity, however, is not
preferred because an elastic composition usually does not provide a
cosmetically appealing product.
The thickener system includes at least one cationic or nonionic
polymer that is solid at ambient temperature. A preferred group of
cationic polymeric thickeners include cationically modified
celluloses, quaternized natural amino-functional polymers, and
polymers based on ethylenically unsaturated monomers selected from
the group of acrylates, acrylamides, vinyl lactams, vinyl acetates,
methyl vinyl ethers, styrene, and acrylonitrile. A preferred group
of nonionic polymeric thickeners include modified celluloses,
associative polymers based on nonionic ethylenically unsaturated
monomers wherein at least one comonomer has at least 16 carbon
atoms, and polymers based on ethylenically unsaturated monomers
selected from the group of acrylates, acrylamides, vinyl lactams,
vinyl acetate and its hydrolyzed derivatives, methyl vinyl ethers,
styrene, and acrylonitrile.
Such polymers can be classified as soluble, swellable, or
associative in the hydroalcoholic solvent system. Some polymers may
fall into one or more of these classes. For example, certain
associative polymers can be soluble in the hydroalcoholic solvent
system. Whether they are considered soluble, swellable, or
associative in the hydroalcoholic solvent system, suitable polymers
for use in the compositions of the present invention are those that
are not capable of forming water-resistant films. Such polymers are
not desirable because they would produce surgical hand preparations
and antimicrobial hand lotions, for example, that could not be
easily washed off with water after being applied and dried.
As used herein, a soluble polymer is one that in dilute solution
(i.e. about 0.01-0.1% by weight in the desired hydroalcoholic
solvent system), after heating for a sufficient time to ensure
solubilization of any potentially soluble components, has no
significant observable particles of greater than about 1 micron in
particle size, as determined by light scattering measurements
using, for example, Malvern Masterisizer E Laser Particle Size
Analyzer available from Malvern Co., Boston, Mass.
As used herein, a swellable polymer is one that in dilute solution
(i.e. about 0.01-0.1% by weight in the desired hydroalcoholic
solvent system), after heating for a sufficient time to ensure
solubilization of any potentially soluble components, has a
significant (i.e., detectable) number of observable particles of
greater than about 1 micron in particle size, as determined by
light scattering measurements using, for example, Malvern
Masterisizer E Laser Particle Size Analyzer.
As used herein, an associative polymer is one that has greater than
2 hydrophobic chains per polymer molecule of greater than about 16
carbon atoms.
Examples of such polymers are as follows.
Soluble Polymers--Cationic Natural Polymer Derivatives
Cationic modified cellulosic polymers are reported in the
literature to be soluble in water. Such polymers have been found to
be useful in the present invention. When used at lower levels in
combination with the appropriate emollients, no balling occurs as
is often seen with neutral modified cellulose polymers. The most
preferred modified cellulose products are sold under the trade
names "CELQUAT" (National Starch and Chemicals Corp., Bridgewater,
N.J.) and "UCARE" (Amerchol Corporation, Edison, N.J.). "CELQUAT"
is a copolymer of a polyethoxylated cellulose and dimethyldiallyl
ammonium chloride and has the Cosmetic, Toiletry and Fragrance
Association (CTFA) designation Polyquaternium-4. The most preferred
"CELQUAT" polymers are "CELQUAT" SC-230M and H-100. "UCARE" is a
polymeric quaternary ammonium salt of hydroxyethylcellulose and a
trimethyl ammonium chloride substituted epoxide and has the CTFA
designation Polyquaternium-10. The preferred "UCARE" polymers have
a high degree of cationic substitution. The most preferred "UCARE"
polymer is "UCARE" JR-30M.
An alkyl modified quaternary ammonium salt of hydroxyethyl
cellulose and a trimethyl ammonium chloride substituted epoxide has
also been found to be useful. The polymer conforms to the CTFA
designation Polyquaternium 24 and is commercially available as
"QUATRISOFT" LM-200 from Amerchol Corp., Edison, N.J.
Soluble Polymers--Cationic Synthetic Polymers
Synthetic cationic linear polymers useful in the present invention
are preferably quite high in cationic charge density--generally
having greater than 10% by weight cationic monomer, preferably
greater than 25% by weight, and more preferably greater than 50% by
weight. This ensures a good cosmetic feel and may actually improve
hydroalcoholic solubility. In general, the polymers useful in the
present invention have sufficient molecular weight to achieve
thickening at generally less than about 5% by weight polymer but
not too high that the lotion/cream feels slimy and stringy. While
the composition of the polymer will dramatically affect the
molecular weight at which sufficient thickening will occur, the
polymers generally have a molecular weight of about 250,000 daltons
to about 3,000,000 daltons, more preferably about 500,000 daltons
to about 1,000,000 daltons. The homopolymers are comprised of one
of the following monomers: methacryloyloxyalkyl trialkyl ammonium
salt, acryloyloxyalkyl trialkyl ammonium salt, and quaternized
dialkylaminoalkylacrylamidine salt. Preferably the polymers are
copolymers comprised of at least two monomers selected from the
group: trialkylaminoalkyl acrylate and methacrylate salts,
dialkyldiallyl ammonium salts, acrylamidoalkyltrialkyl salts,
methacrylamidoalkyltrialkyl salts, and alkyl imidazolinium salts,
N-vinyl pyrrolidinone, N-vinyl caprolactam, methyl vinyl ether,
acrylates, methacrylates, styrene, and acrylonitrile. Typically,
for the salts the counterions are preferably F.sup.-, Cl.sup.-,
Br.sup.-, and CH.sub.3 (CH.sub.2).sub.n SO.sub.4.sup.- where
n=0-4.
A variety of quaternary copolymers of varying quaternization, can
be synthesized based on homo or copolymers of amino acrylates with
methyl, ethyl or propyl side chains. These monomers could also be
copolymerized with other nonionic monomers including quaternary
acrylic homopolymers, such as homopolymers of 2-methacryloxyethyl
trimethylammonium chloride and 2-methacryloxyethyl methyl diethyl
ammonium bromide; and copolymers of quaternary acrylate monomers
with a water-soluble monomers, such as Petrolite Product No.
Q-0043, a proprietary copolymer of a linear quaternary acrylate and
acrylamide at high molecular weight (4-5 million MW).
Another useful soluble cationic polymer is
N,N-dimethylaminopropyl-N-acrylamidine (which is quaternized with
diethylsulfate) bound to a block of polyacrylonitrile. This block
copolymer is available as "Hypan QT-100" from Lipo Chemicals Inc.,
Paterson, N.J. It is quite effective at thickening hydroalcoholic
systems and has a good cosmetic feel. This polymer as received,
however, has an objectionable amine odor. The odor could probably
be masked with the proper fragrance, but is preferably removed
prior to formulation (e.g., with a solvent cleaning process) so
that the formulation can be supplied without fragrance.
Soluble Polymers--Nonionic
A variety of cellulosic ethers are reported in the literature to be
soluble in water. Such polymers have demonstrated the ability to
viscosify hydroalcoholic solvent systems containing greater than
about a 50:50 ratio of alcohol to water. Materials in this class
that are nonionic and have been shown to be useful include:
methylhydroxypropylcellulose, available as "BENECEL MP 943" from
Aqualon, Wilmington, Del.; hydroxypropylcellulose, available as
"KLUCEL" (LF, GF, MF, HF) from Aqualon, Wilmington, Del.; and
hydroxybutylmethylcellulose (3.5% hydroxybutyl and 30% methoxyl)
from Scientific Polymer Products, Ontario, N.Y.
Swellable Polymers
Many swellable polymers, which are slightly crosslinked, function
as viscosifiers in hydroalcoholic solvent systems. In general,
these swellable polymers are preferred because they tend to be far
less "slimy" going on and once the hands perspire and are exposed
to water after treatment. Excessive crosslinking will result in
polymers that do not swell sufficiently to increase the viscosity
of the composition. In order to ensure adequate swelling, if a
chemical crosslinker is used, the concentration of crosslinker is
quite low, e.g., less than about 1000 ppm, and preferably less than
500 ppm, based on the weight of the dry polymer.
A class of crosslinked polymers suitable for use in this invention
are comprised of acrylamide and at least one other quaternary
monomer selected from the group of trialkylaminoalkylacrylate and
methacrylate salts, dialkyldiallyl ammonium salts,
acrylamidoalkyltrialkyl ammonium salts, methacrylamidoalkyltrialkyl
ammonium salts, and monomers comprising imidazolinium salts. The
counterions are preferably F.sup.-, Cl.sup.-, Br.sup.-, and
CH.sub.3 (CH.sub.2).sub.n SO.sub.4.sup.- where n=0-4. Other
comonomers may also be added including N-vinyl pyrrolidone,N-vinyl
caprolactam, methyl vinyl ether, acrylates, methacrylates, styrene,
and the like. A particularly preferred polymer is comprised of a
poly(2-methacryloxyethyl trimethyl ammonium chloride)
polydimethylaminoethyl methacrylate, which conforms to the CTFA
designation Polyquaternium 37. Another preferred polymer is
comprised of acrylamide and methacryloyloxyethyl trimethyl ammonium
chloride, which conforms to the CTFA designation Polyquaternium 32.
These are commercially available from Allied Colloids Inc. of
Suffolk, Va. as "SALCARE" SC95, SC96, and SC92.
Other swellable polymers (i.e., slightly crosslinked polymers) can
be prepared using ionizing radiation to crosslink. For examples,
polymers comprising N-vinyl lactams, such as N-vinyl pyrrolidone,
when exposed to gamma radiation increase in molecular weight and
may actually crosslink. This crosslinking allows for more efficient
thickening (less polymer required to achieve a certain viscosity)
and an improved cosmetic feel. Other polymers that when exposed to
gamma radiation result in crosslinking, include polymers such as
"LUVIQUAT HM 552" (copolymers of vinylimidazolium methochloride and
vinylpyrrolidone, which conforms to the CTFA designation
Polyquaternium-16), and "GAFQUAT HS-100"
(vinylpyrrolidone/methacrylamidopropyltrimethylammonium chloride
copolymer which conforms to the CTFA designation
Polyquaternium-28).
Chemical crosslinking using polyunsaturated monomers such as
diallyl maleate may also prove useful. Other suitable crosslinkers
are multi-ethylenically unsaturated compounds wherein the ethylenic
groups are vinyl groups (including substituted vinyl groups, such
as isopropenyl groups), allyl groups, and/or methallyl groups,
which groups are bonded to nitrogen or oxygen atoms. Vinyl, allyl,
and methallyl groups as used herein include substituted
derivatives. Exemplary compounds include divinyl, diallyl, or
dimethallyl esters, ethers, amides, or ureas. Specific examples are
disclosed in U.S. Pat. No. 5,225,473 (Duan) and U.S. Pat. No.
4,931,282 (Asmus et al.).
A range of crosslinked polyvinylpyrrolidone (PVP) materials have
been prepared via covalent crosslinking with diallyl maleate or by
radiation crosslinking of linear PVP powders. Crosslinked PVP
prepared under these techniques can produce colloidal particles
which are highly swellable in hydroalcoholic solutions and thereby
produce viscous solutions. The polymers are also nonionic and have
excellent compatibility with chlorhexidine digluconate.
Associative Polymers
Associative polymers can be used in the thickening system of the
compositions of the present invention. Such polymers thicken as a
result of hydrophobic or Van de Waals association of hydrophobic
side chains. Such associative polymers can form viscous to gelled
hydroalcoholic solutions despite their relatively low molecular
weights. Polymers that are alcoholic soluble can be modified by the
addition of a long chain hydrophobic group. A preferred class of
such associative polymers are based on nonionic ethylenically
unsaturated monomers wherein at least one comonomer has at least 16
carbon atoms.
An example is cetyl hydroxyethylcellulose, available as "NATROSOL
PLUS" from Aqualon, which utilizes an associative mechanism to
enhance the viscosity it produces. Grafted side chains of cetyl
alkyl groups can associate with neighboring alkyl hydrophobes.
These interpolymer associations can dramatically increase the
viscosification efficiency of the polymer. In hydroalcoholic
systems of the present invention, the interpolymer associations can
greatly improved if longer chain hydrophobic groups were used in
place of the cetyl groups, since the C16 groups are not as
insoluble as longer chain alkyls. For example, alkyl chains
containing 18-31 carbon atoms, preferably 20-34 carbon atoms,
provide particularly desirable polymeric thickeners in a
hydroalcoholic solvent system containing at least about a 65:35
alcohol to water ratio. Long chain alkenyl and aralkyl groups may
also be suitable.
Purity of Polymeric Thickeners
Attention may need to be paid to the purity of the thickener
systems. For example, certain highly charged polymeric thickeners
of the present invention are detrimentally effected by
incorporation of ionic materials such as salts. Even low level
ionic contaminants can significantly lower the viscosity. For this
reason, many commercially available polymers are preferably cleaned
prior to use such that there are substantially no excess ions for
optimum performance. As used herein, "excess ions" refers to ions
(other than the cations and counterions present in cationic
polymers) that can be removed from the polymer by repeatedly
washing with solvent.
Quaternary thickeners are particularly sensitive to excess ions in
solution. For example, in embodiments where the secondary
antimicrobial agent is a charged molecule such as a chlorhexidine
salt (e.g., chlorhexidine digluconate), the excess ions reduce the
viscosification efficiency of the quaternary thickener such that at
a concentration of at least about 0.5% by weight chlorhexidine
digluconate it is very difficult to formulate highly viscous
systems above 60% lower alcohol. Commercial quaternary thickeners
such as "SALCARE SC95" (referred to herein also as DMAEMA Q) have
been found to have excess ions that prohibit their ability to
thicken a 75% ethanol solution. By removing these excess ions, such
as by repeated precipitations, for example, the excess salts and
the polymer can effectively thicken even 75% alcohol solutions.
Thus, for example, by removing excess ions, compositions containing
a chlorhexidine salt in at least about 0.5% by weight, based on the
total weight of the composition, can be thickened with a cationic
polymeric thickener to a viscosity of greater than about 60,000 cps
at 23.degree. C.
The excess ions in solution can be monitored by evaluating cleaned
and uncleaned polymer in 35% ethanol solutions with an ionic
conductivity meter. The difference in the ionic conductivity of the
cleaned verses uncleaned polymer is due to excess ions. It is
desired that the ionic conductivity contribution of excess ions in
the polymeric thickener, as measured using a Model 76 Conductivity
Meter by Engineered Systems & Designs, Newark, Del., be less
than about 50% of the ionic contribution of the polymer, preferably
less than about 35%, more preferably less than 15%, and most
preferably less than 5%, as determined in a desired hydroalcoholic
solvent system (without any other additives). Generally, this is
done in 35% ethanol/ 65% water, however, if the polymer is
insoluble in this solvent system, it is carried out in 100% water.
In either situation, the polymer should be conditioned in the
solvent for 24 hours at 60.degree. C. to extract the ions prior to
conductivity testing. For the DMAEMA Q system, it is desired that
the ionic conductivity in 35% ethanol, at 2.5% polymer loading be
below 1,200 .mu.mho, and preferably be below 1,000 .mu.mho, and
more preferably be below 900 .mu.mho and most preferably be below
800 .mu.mho.
Antimicrobials
In addition to the lower alcohols present in the composition of the
present invention, other antimicrobials may be added to enhance the
antimicrobial action of the compositions of the present invention.
Such antimicrobials are referred to herein as "secondary
antimicrobials." This may be particularly desirable in critical
uses such as presurgical hand scrubs or presurgical patient skin
scrub replacements. Suitable additional antimicrobials include
iodine and its complexed forms such as povidone/iodine,
chlorhexidine salts such as chlorhexidine digluconate (CHG),
parachlorometaxylenol (PCMX), hexachlorophene, phenols, surfactants
comprising a long chain hydrophobe (C12-C22) and a quaternary
group, triclosan, "LAURICIDIN" glyceryl monolaurate, quaternary
silanes, hydrogen peroxide, phenols, silver, silver salts such as
silver chloride, silver oxide and silver sulfadiazine and the like.
In order to reduce chances for irritation and yet maintain
efficacy, the antimicrobial level should be adjusted to the minimum
level which maintains a low bacteriological count for 6 and most
preferably for 12 hours after application.
The most preferred secondary antimicrobial is chlorhexidine since
it is capable of ensuring long term antimicrobial efficacy. If
chlorhexidine is added to the present invention it is preferably
present as a soluble salt. The diacetate and digluconate salts are
preferred. The most preferred antimicrobial is chlorhexidine
digluconate (CHG). CHG is preferably present at a concentration of
about 0.05-5.0%, more preferably about 0.1-3%, even more preferably
about 0.25-2%, and most preferably about 0.5-1%, by weight, based
on the total weight of the composition. Chlorhexidine is a
bis(diguanide) and therefore is very basic and is capable of
forming multiple ionic bonds with anionic materials.
Optional Ingredients
In addition to alcohol, water, thickener system, and antimicrobial
agents, the compositions of the present invention may optionally
include ingredients such as pH buffers, emollients, antioxidants,
fragrances, pharmaceutical agents, and propellants. It may also be
beneficial to incorporate certain emulsifiers into the compositions
of the present invention to ensure long-term stability of systems
incorporating hydrophobic emollients.
Emollients
Emollients are typically added to hand lotions or hand preps
because they act to increase the moisture content of the stratum
corneum. Emollients are generally separated into two broad classes
based on their function. The first class of emollients are
lipophilic which function by forming an occlusive barrier to
prevent water evaporation from the stratum corneum. The second
class of emollients penetrate into the stratum corneum and
physically bind water to prevent evaporation. The first class of
emollients is subdivided into compounds which are waxes at room
temperature and compounds which are liquid oils. The second class
of emollients includes those which are water soluble and are often
referred to as humectants.
For the purposes of this invention the emulsifier system is
considered separate and distinct from any emollients which may be
added even though it is recognized that the emulsifiers may
function as occlusive emollients and aid in maintaining or
improving the skin condition. Emollients are included in a
preferred embodiment of the invention and preferably comprise
between about 1% and about 30%, more preferably between about 2%
and about 20% and most preferably between about 3% and about 12% by
weight of the formulation.
Emollients may be selected from any of the classes known in the
art. A general list of useful emollients appears in U.S. Pat. No.
4,478,853 and EPO patent application 0 522 624 A1 and in the CTFA
Cosmetic Ingredient Handbook published by The Cosmetic, Toiletry,
and Fragrance Association, Wash. D.C. (1992) under the listings
"Skin Conditioning agents," "emollients," "humectants,"
"miscellaneous" and "occlusive," each of these references is hereby
incorporated by reference. Preferred compositions of the present
invention include both wax and liquid emollients.
In preferred embodiments, emollients are chosen from the following
nonlimiting list of general emollients, occlusive lipophilic
emollients and humectants. Examples of general emollients include
short chain alkyl or aryl esters (C1-C6) of long chain straight or
branched chain alkyl or alkenyl alcohols or acids (C8-C36) and
their polyethoxylated derivatives; short chain alkyl or aryl esters
(C1-C6) of C4-C12 diacids or diols optionally substituted in
available positions by --OH; alkyl or aryl C1-C9 esters of
glycerol, pentaerythritol, ethylene glycol, propylene glycol, as
well as polyethoxylated derivatives of these and polyethylene
glycol; C12-C22 alkyl esters or ethers of polypropylene glycol;
C12-C22 alkyl esters or ethers of polypropylene glycol/polyethylene
glycol copolymer; and polyether polysiloxane copolymers. In
addition to many of the emulsifiers of preferred emulsifier
systems, additional examples of occlusive emollients include cyclic
dimethicones, polydialkylsiloxanes, polyaryl/alkylsiloxanes, long
chain (C8-C36) alkyl and alkenyl esters of long straight or
branched chain alkyl or alkenyl alcohols or acids; long chain
(C8-C36) alkyl and alkenyl amides of long straight or branched
chain (C8-C36) alkyl or alkenyl amines or acids; hydrocarbons
including straight and branched chain alkanes and alkenes such as
squalene, squalane, and mineral oil; polysiloxane polyalkylene
copolymers, dialkoxy dimethyl polysiloxanes, short chain alkyl or
aryl esters (C1-C6) of C12-C22 diacids or diols optionally
substituted in available positions by OH; and C12-C22 alkyl and
alkenyl alcohols. Nonlimiting examples of preferred humectant type
emollients include glycerol, propylene glycol, dipropylene glycol,
polypropylene glycol, polyethylene glycol, sorbitol, pantothenol,
gluconic acid salts and the like.
Although the thickener system is responsible for the stability and
overall consistency of compositions of the present invention,
emollients may also affect the viscosity and stability of a
composition. It is anticipated that a single emollient may be added
to the present invention or two or more emollients may be added to
the composition. A wide range of emollients may be added to the
formulations of the present invention. Preferably wax and oil type
emollients along with water soluble emollients are used. In a
preferred embodiment, emollient systems are comprised of humectants
in addition to occlusive wax and oil emollients in concentrations
which achieve a moisturizing but not greasy composition which
maintains and improves the condition of the skin upon repeated use.
Ideally, emollients are non-comedogenic and are chosen to ensure no
skin irritation or sensitization reaction occurs. This is
particularly critical since the composition of the present
invention will likely be worn in an occluded condition under
surgical gloves. Furthermore, emollients should be chosen which do
not affect the integrity of the glove material. For example, since
hydrocarbon emollients such as mineral oil and petrolatum can
detrimentally affect the tear strength of surgical gloves, these
emollients may need to be avoided for compositions employed as
presurgical disinfectants.
Certain emollients which are insoluble in the hydroalcoholic
solvent can be emulsified in what is believed to be a separate and
distinct emulsion. These emollients have little affect on the melt
temperature of a composition. For example, certain cyclic
silicones, polysiloxanes, and dialkoxypolysiloxanes can be
emulsified in hydroalcoholic solvents using polyether/polysiloxane
copolymers surfactants.
The following are nonlimiting examples of emulsifier/emollient
components which improve thickening/stability of compositions of
the present invention.
a. Certain wax emulsifiers/emollients have been found to be
particularly useful and include solid waxy esters such as: Myristyl
Myristate, Cetyl Palmitate, Myristyl Stearate, Stearyl Behenate,
Behenyl Isostearate, Isostearyl Behenate, Behenyl Behenate, Lauryl
Behenate, Behenyl Erucate. These have the following formula:
R.sup.12 --CO.sub.2 --R.sup.13 wherein R.sup.12 is an alkyl or
alkenyl group of at least 14 carbon atoms, and R.sup.13 is an alkyl
or alkenyl group of at least 4 carbon atoms.
b. Long chain hydrocarbon di-esters or tri-esters of polyhydric
alcohols with a melting point of greater than 23.degree. C.,
including solid esters such as glycerol tribehenate and sorbitan
tristearate.
c. Pure lanolins and lanolin derivatives (e.g., hydrogenated
lanolin), which provide excellent emolliency but can also improve
the stability of the emulsion when used in combination with oil
emollients.
d. Petrolatums, which are mixtures of oily and waxy long chain
hydrocarbons, provide excellent emolliency, and can also improve
the stability of the emulsion when used in combination with oil
emollients.
e. Microcrystalline waxes and branched hydrocarbon waxes with a
melting point of greater than 50.degree. C. and a molecular weight
of greater than 400. Examples of this includes, but is not limited
to, "VYBAR 103" branched hydrocarbon with a number average
molecular weight of 2800, and "ULTRAFLEX" microcrystalline wax,
both of which are available from Petrolite Corp. of Tulsa,
Okla.
f. Oxidized waxes and modified hydrocarbon waxes, which are
prepared from waxes modified by oxidation, salts of oxidized waxes,
maleic anhydride adducts of polyolefins and urethane derivatives of
oxidized synthetic or petroleum waxes. Applicable waxes could
include Petrolite's Cardis or Petronauba microcrystalline and
polyethylene-based oxidized products, Polymekon (salts) and Ceramer
(anhydride adducts).
g. Fully saturated homopolymers of polyethylene, or copolymers of
various alkene monomers having a molecular weight at or below 3,000
with a melting point below 130.degree. C. and low melt viscosities.
Applicable waxes could include "POLYWAX" available from Petrolite
Corp.
Fragrances
The compositions of the present invention may also comprise a
fragrance. If fragrances are included the fragrances must be chosen
carefully since some fragrances are known to cause skin irritation
and/or sensitization reactions.
Propellants
The compositions of the present invention may also be formulated
into an aerosol foam or mousse by addition of an appropriate
propellant. The propellant must be chosen to ensure proper delivery
from the container to prevent clogging of the valve. The propellant
can be chosen from chlorofluorocarbons (CFCs),
hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs),
perfluorinated alkanes, and lower alkanes (C1-C5) as well as
nitrous oxide dimethyl ether and other solvent-soluble propellants.
Preferred propellants are lower alkanes such as propane, butane,
and isobutane since these result in a dramatic loss in viscosity
making the formulation easy to dispense. A 70:30 mixture of
propane/isobutane is a particularly preferred embodiment. In order
to produce an aerosol composition the antimicrobial lotion is first
formulated and charged into an appropriate pressure rated
container. If convenient, the formulation may be heated above the
melt temperature in order to facilitate filling. The propellant is
then added under pressure at approximately 2-30% preferably 3-20%
by volume. The propellant may form a separate layer or may remain
emulsified in the composition.
Pharmaceutical Agents
Pharmaceutical agents (e.g., medicaments, drugs, prodrugs, etc.)
suitable for use in compositions of the present invention are
compounds that are intended to be delivered transdermally (i.e.,
into the skin and/or through the skin into the circulatory system)
to a mammal to alter biological function to treat, cure, and/or
prevent disease or abnormal conditions.
Suitable pharmaceutical agents exhibit an optimal combination of
such properties as water solubility, polarity, structure, and
molecular weight. For instance, molecular weights are typically
between about 100 daltons and about 5000 daltons, and preferably
between about 200 daltons and about 1200 daltons. Examples of
suitable pharmaceutical agents include those described in U.S. Pat.
No. 4,752,612 (Saito et al.).
Suitable pharmaceutical agents include antiinflammatory drugs, both
steroidal (e.g., hydrocortisone, prednisolone, triamcinolone) and
nonsteroidal (e.g., naproxen, piroxicam); antibacterials (e.g.,
penicillins such as penicillin V, cephalosporins such as
cephalexin, erythromycin, tetracycline, gentamycin, sulfathiazole,
nitrofurantoin, and quinolones such as norfloxacin, flumequine, and
ibafloxacin); antiprotazoals (e.g., metronidazole); antifungals
(e.g. nystatin); vasodilators (e.g., nitroglycerin); calcium
channel blockers (e.g., nifedipine, diltiazem); bronchodilators
(e.g., theophylline, pirbuterol, salmeterol, isoproterenol); enzyme
inhibitors such as collagenase inhibitors, protease inhibitors,
elastase inhibitors, lipoxygenase inhibitors (e.g., A64077), and
angiotensin converting enzyme inhibitors (e.g., captopril,
lisinopril); other antihypertensives (e.g., propranolol);
leukotriene antagonists (e.g., ICI204,219) antiulceratives such as
H2 antagonists; steroidal hormones (e.g., progesterone,
testosterone, estradiol, levonorgesterel); antivirals and/or
immunomodulators (e.g.,
1-isobutyl-1H-imidazo[4,5-c]quinolin-4amine,
1-(2-hydroxyl-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-4-amine,
acyclovir); local anesthetics (e.g., benzocaine, propofol);
cardiotonics (e.g., digitalis, digoxin); antitussives (e.g.,
codeine, dextromethorphan); antihistamines (e.g., diphenhydramine,
chlorpheniramine, terfenadine); narcotic analgesics (e.g.,
morphine, fentanyl); peptide hormones (e.g., human or animal growth
hormones LHRH); cardioactive products such as atriopeptides;
proteinaceous products (e.g., insulin); enzymes (e.g., anti-plague
enzymes, lysozyme, dextranase), antinauseants (e.g., scopolamine);
anticonvulsants (e.g., carbamazepine); immunosuppressives (e.g.,
cyclosporine); psychotherapeutics (e.g., diazepam); sedatives
(e.g., phenobarbital); anticoagulants (e.g., heparin); analgesics
(e.g., acetaminophen); antimigraine agents (e.g., ergotamine,
melatonin, sumatriptan); antiarrhythmic agents (e.g., flecainide);
antemetics (e.g., metoclopramide, ondansetron); anticancer agents
(e.g., methotrexate); neurologic agents such as anxiolytic drugs;
hemostatics; antiobesity agents; nicotine; and the like, as well as
pharmaceutically acceptable salts and esters thereof.
The pharmaceutical agent is present in a transdermal delivery
device of the invention in a therapeutically effective amount,
i.e., an amount effective to bring about a desired therapeutic
result in the treatment of a condition. The amount that constitutes
a therapeutically effective amount varies according to the
particular pharmaceutical agent incorporated in the device, the
condition being treated, any pharmaceutical agent being
coadministered with the selected pharmaceutical agent desired
duration of treatment, the surface area of the skin over which the
device is to be placed, the type of device being utilized, the
choice of excipients, and other components of the device.
Penetration Enhancers
Additional compounds other than the lower alcohol or components of
the emulsifier system may also be present in the composition to
further boost the penetration of a particular pharmaceutical agent.
These penetration enhancers may be present primarily in either the
oil-like phase of the emulsion or the hydroalcoholic phase.
Non-limiting examples of additional penetration enhancers include
C.sub.8 -C.sub.22 fatty acids such as isostearic acid, octanoic
acid, and oleic acid; C.sub.8 -C.sub.22 fatty alcohols such as
oleyl alcohol and lauryl alcohol; lower alkyl esters of C.sub.8
-C.sub.22 fatty acids such as ethyl oleate, isopropyl myristate,
butyl stearate, and methyl laurate; di (lower) alkyl esters of
C.sub.6 -C.sub.8 diacids such as diisopropyl adipate;
monoglycerides of C.sub.8 -C.sub.22 fatty acids such as glyceryl
monolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether;
polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol;
diethylene glycol monomethyl ether; alkylaryl ethers of
polyethylene oxide; polyethylene oxide monomethyl ethers;
polyethylene oxide dimethyl ethers; dimethyl sulfoxide; glycerol;
ethyl acetate; acetoacetic ester; N-alkylpyrrolidone; and terpenes.
Certain emulsifier systems may also significantly increase the flux
of particular pharmaceutical agents. This may be particularly true
of emulsifiers that are in a pure state liquids at skin temperature
such as those having shorter chain hydrophobes (e.g., methyl
laurate), unsaturated hydrophobes (methyl oleate, oleic acid, oleyl
alcohol, glycerol monooleate), and branched hydrophobic hydrocarbon
chains (isostearyl alcohol).
Transdermal Delivery Systems
The compositions of the present invention can be used in a variety
of transdermal delivery systems (e.g., devices). A variety of such
systems have been described. The simplest is a lotion of a
pharmaceutical agent in the composition of the present invention.
Others include matrix devices in which a pharmaceutical agent is
incorporated into the composition of the present invention and
placed within a polymeric material such as a hydrogel layer or
adhesive; reservoir devices in which the pharmaceutical
agent-containing hydroalcoholic composition is delivered to the
skin through a rate-controlling membrane; drug-in-adhesive devices
in which the pharmaceutical agent is placed within the composition
of the present invention as part of an adhesive composition; and
more complex multilaminate devices involving several distinct
layers (e.g., layers for containing the pharmaceutical agent, for
containing excipients, for controlling the rate of release of the
pharmaceutical agent and excipients, and for attaching the device
to the skin). Each of these devices include an adhesive to maintain
contact with the patient's skin and a backing that protects the
device from external factors while in use, thereby forming a
patch.
An exemplary reservoir device comprises a backing, a matrix
containing the composition of the present invention with the
pharmaceutical agent therein, optionally a membrane for controlling
the rate at which the pharmaceutical agent is delivered to the
skin, an adhesive layer, and a release liner.
Alternative Applications for the Compositions
The compositions of this invention may be compounded with UV
absorbers and oils to deliver fast-drying sunscreens.
Antimicrobials such as benzoyl peroxide may also be added to the
formulations and the formulations may be useful as an acne
medication. The systems of this invention may also be formulated
with barrier compounds to form barrier creams and lotions.
Materials which may be added to provide barrier protection for use
as skin barriers to protect against diaper rash include but are not
limited to 0.1 to 60% aldioxa, allantoin, aluminum acetate,
aluminum hydroxide, bismuth subnitrate, boric acid, calamine,
cellulose (microporous), cholecalciferol, cocoa butter, cod liver
oil (in combination), colloidal oatmeal, cysteine hydrochloride,
dexpanthenol, dimethicone, glycerin kaolin, lanolin (in
combination), live yeast cell derivative, mineral oil, peruvian
balsam, peruvian balsam oil, petrolatum, protein hydrolysate
(1-leucine, 1-isoleucine, 1-methionine, 1-phenylalanine, and
1-tyrosine), racemethionine, shark liver oil, sodium bicarbonate,
sulfur, talc, tannic acid, topical starch, vitamin A, white
petrolatum, zinc acetate, zinc carbonate and zinc oxide.
Formulations are also contemplated containing antifungal agents for
treating fungal infections of the skin such as athlete's foot and
the like. The compositions of the present invention can be
dispensed in a discreet, substantially uniform amount using the
dispensers disclosed in Applicants' Assignees' Copending U.S.
patent application Ser. No. 08/668,198, filed Jun. 21, 1996,
entitled "Dispenser for Antimicrobial Liquids" and Ser. No.
08/668,270, filed Jun. 21, 1996 entitled "Drip Resistant Nozzle for
a Dispenser".
Methods of Preparation
The compositions of the present invention may be prepared by a
variety of techniques. For example, the process can often be as
simple as adding the polymer to the hydroalcoholic solvent at a
temperature above the melting point of any solid emulsifiers,
mixing briefly and cooling. For compositions containing insoluble
emollients and/or emulsifiers, it may be beneficial to mix the
components under high shear (e.g., using a homogenizer).
In general it works well to melt any solid components such as
emulsifiers with aqueous-insoluble emollients together in one
vessel and add these to the hydroalcoholic solvent and any aqueous
miscible emollients along with the polymeric thickening agent. It
may be beneficial to heat the system. The processing variables
including amount and intensity of high shear mixing, rate of
cooling, and order of addition are easily determined by one skilled
in the art.
Test Methods
Viscosity
In the following Examples (except where indicated) viscosity was
measured at 23.degree. C. at ambient pressure using a Brookfield
LVDV-I.sup.+ viscometer equipped with a model D Brookfield
heliopath and T spindles B-F. The spindle and speed was chosen for
each particular sample such that the viscometer was operating in
the middle of its range. All samples were allowed to equilibrate at
23.degree. C. for 24 hours prior to measurement. Preferably the
viscosity is taken at the lowest speed possible while staying
within 20-80% of the viscometer range and more preferably between
30-70% of the range. In all cases the sample size and container
geometry was chosen to ensure that there were no wall effects. By
"wall effects" it is meant the viscosity value is not affected by
the container and is essentially equivalent to the viscosity taken
in an infinitely large container. For this reason lower viscosity
samples required a larger sample size to accommodate the larger
spindles. The following table outlines preferred spindles for
various sample viscosities.
Sample Viscosity T Spindle to Use 1,000-100,000 B 10,000-200,000 C
50,000-500,000 D 100,000-1,250,000 E 500,000-3,000,000 F
The viscosity of each sample was taken as the highest relatively
stable reading achieved on the first path the spindle traversed
using the heliopath adapter.
Stability
The stability of samples was measured 24 hours after conditioning
at ambient conditions by placing 12 ml of a formulation that formed
a lotion/cream in a 15 ml graduated centrifuge tube. The tube was
then centrifuged in a Labofuge B (Heraeus Sepatech GmbH, Model
2650, rotor 2150 and buckets #2101) at 2000 rpm (1545.times.g when
measured at the longitudinal midpoint of the sample tube) for 30
minutes at 23.degree. C. Stability is recorded as a volume percent
separation in the Examples below.
Minimum Inhibitory Concentration (MIC)
An overnight culture of E. coli ATCC 8739 (lab strain 223) and/or
S. Aureus ATCC 14154 (lab strain 502) grown on trypticase soy agar
plates was resuspended in Mueller-Hinton Broth to a cell density of
0.6-1.2.times.10.sup.6 colony forming units per milliliter.
Chlorhexidine samples were prepared by adjusting CHG to 512
.mu.g/ml in Mueller-Hinton Broth and serially diluting in two-fold
steps in Mueller-Hinton Broth. The CHG-containing Mueller-Hinton
Broth was placed in 96-well sterile microliter plates and each well
was inoculated with the bacteria. The plates were then incubated
for 24-48 hours at 37.degree. C. Bacterial growth was determined
visually by comparing the plates. The MIC was determined as the
lowest concentration of CHG that resulted in complete kill of the
test organism.
EXAMPLES
The following Examples are provided to illustrate the invention and
are not intended to limit the scope of the invention.
Example 1
Quaternary Cellulose Thickeners and Viscosity
A series of antimicrobial compositions was prepared using the
following base formula:
Component Wt. % Lanette 14 (Myristyl alcohol).sup.1 0.5 Arlamol E
(PPG-15 stearyl ether).sup.2 0.5 Ethanol/Water (65:35 by wt) 99.0
.sup.1 Witco, Humko Chemical Div., Memphis, Tenn. .sup.2 ICI
Surfactants, Wilmington, Delaware
To this base emollient/solvent system was added "CELQUAT" polymer
and chlorhexidine digluconate (CHG) in the amounts shown in the
table below. The polymer was added as a powder, shaken vigorously
and placed in a 60.degree. C. oven overnight to ensure complete
dissolution. The CHG was added as a 20% (weight by volume) solution
in water in the amount necessary to reach the final concentration
indicated.
Concentration Conc. CHG Viscosity* Polymer (Wt %) (Wt. %) (cps)
CELQUAT 230M 1.0 0 1600 1.0 0.5 1600 1.0 1.0 1600 2.0 0 31000 2.0
0.5 34000 2.0 1.0 33000 CELQUAT H-100 2.0 0 2000 2.0 0.5 2000 2.0
1.0 1800 3.0 0 8800 3.0 0.5 9400 3.0 1.0 7700 *Brookfield Viscosity
using a Brookfield LVT viscometer with spindle #3.
The results indicate that both "CELQUAT" polymers are capable of
thickening a hydroalcoholic solvent system. Also, the viscosity is
not significantly affected by the presence of CHG. The results also
indicate that "CELQUAT 230M" is a much more effective thickener,
achieving significantly higher viscosity at 2% by weight than the
"CELQUAT H-100" at 3% by weight. The higher viscosity at lower
solids content generally results in better cosmetic properties.
Example 2
Quaternary Cellulose Thickeners and Effect of Solvent and Emollient
System
The following formulations were made in a similar fashion as that
described in Example 1 except that both the CHG and silicone
detackifier (if present) were added after heating.
Formula A B C D E F G 200 Proof 61.1 68.8 61.3 61.0 63.1 63.1 61.4
Ethanol Distilled 30.4 24.7 33.0 33.3 29.5 29.5 30.6 Water 20% CHG
5.0 5.0 5.0 5.0 5.0 5.0 5.0 Arlamole E 0.75 0.75 0.75 0.75 0.75
0.75 0.75 Lanette 14 0.75 0.75 0.75 0.75 0.75 Celquat 2.0 2.0 2.0
2.0 2.0 2.0 2.0 230 M Ucare JR- 1.0 30 M Ceraphyl 0.75 1.0
424.sup.1 Abil EM-90.sup.2 0.94 200 Fluid, 0.75 0.75 200 ctks.sup.3
.sup.1. Myristyl Myristate available from ISP Van Dyk Inc.
Belleville, NJ .sup.2. Cetyl dimethicone copolyol; Goldschmidt
Chemical Corp., Hopewell VA. .sup.3. Polydimethylsiloxane available
from Dow Corning Corp., Midland MI
The viscosity of Samples A and B were measured on a Brookfield LVT
viscometer using spindle #3 with the following results:
Spindle Speed Viscosity Sample (RPM) (cps) A 1.5 45600 3.0 34200 B
1.5 46800 3.0 36800
These results indicate that the viscosity is not dependent on the
level of ethanol within the range 64:36 to 71:29 ethanol:water. The
shear rate appears to influence the viscosity since at higher
viscometer rotational speeds the viscosity is reduced.
Samples A and B had a somewhat slimy feel during application and
became tacky as the lotion dried and even after drying. Samples C
and D also had a somewhat slimy feel during application but sample
C was only slightly tacky as the lotion dried and after drying.
Sample D was non-tacky once dried. Samples E and F were
significantly less tacky and had a nice feel when dry. Sample G was
somewhat slimy going on but had a nice feel when dry and did not
ball.
Example 3
Quaternary Acrylates
The quaternary ethylenically unsaturated monomer containing
polymers such as quaternary acrylates or quaternary acrylate
copolymers are quite sensitive to ion concentration and can suffer
dramatic viscosity losses upon addition of minor concentrations of
salts. The graph shown in FIG. 1 illustrates the viscosity loss of:
a. "SALCARE SC92," a copolymer of acrylamide and
methacryloyloxyethyl trimethyl ammonium chloride having CTFA
designation Polyquaternium 32. b. "SALCARE SC95," a homopolymer of
methacryloyloxyethyl trimethyl ammonium chloride having CTFA
designation Polyquaternium 37.
Both of these products are supplied as 50% polymer concentration in
a mineral oil inverse emulsion. For each polymer 4 g of the polymer
emulsion (2 grams of polymer) was added to 96 grams of warm
(60.degree. C.) 68:32 ethanol water and shaken vigorously. The
mixture was allowed to sit overnight. CHG was added as a 20%
aqueous solution in small aliquots and the viscosity was measured
after each addition using a Brookfield DV-I+ with a model D
heliopath and a T spindle. The viscosity is shown in FIG. 1.
FIG. 1 illustrates that as CHG is added the viscosity progressively
drops. The viscosity of "SALCARE SC92" is greater than that of SC95
at each concentration. The viscosity achieved may be further
increased by ensuring minimum incorporation of salts or salt
contamination. For example, as received from the supplier, "SALCARE
SC92" contains ionic contaminants. If these are removed by the
procedure in Example 9, a higher viscosity composition results.
This is shown below for 68:32 ethanol/water containing 0.5% CHG and
4% polymer.
Polymer Viscosity (cps).sup.1 SALCARE SC92 (As received) 15,000
SALCARE SC92 (cleaned) 84,000 .sup.1 Measured using a Brookfield
DV-I+ with a model D heliopath and a T spindle.
Example 4
Compositions Containing "SALCARE SC-92" Polymer
The following formulation was prepared using "SALCARE SC-92" as the
thickener. The emollients were added to the ethanol/water solution
and heated to 65 C. for 1 hour at which point all waxes were
melted. The "SALCARE" was added and the contents shaken vigorously
and then mixed well using a high shear rotor/stator mixer. The
formulation was allowed to sit overnight prior to evaluation.
Emollient Trade Name Chemical Description Wt. % POLAWAX A31
ceteareth-20, cetearyl alcohol 1.5 GANEX V220 copolymer
NVP/1-eicosene, 0.38 MW = 8600 CERAPHYL 28 cetyl lactate 0.74
LANETTE 14 myristyl alcohol 0.74 BERNEL Ester 2014
arachidylmyristate 0.56 LIPOVOL MOS130 dipentaerythrityl
hexacaprylate/ 0.56 hexacaprate tridecyl stearate,
tridecyltrimellitate LEXOL PG865 propylene glycol
dicaprylate/dicaprate 0.56 SALCARE SC92 Polyquaternium 32 (50% in
mineral oil) 2.4
This formulation had a thick rich feel during application. The
lotion dried rapidly without tackiness and had a nice feel once
dried.
Example 5
Compositions Containing "HYPAN QT-100" or "SALCARE SC-92"
The following formulations were prepared using "HYPAN QT-100" and
"SALCARE SC-92" as the thickeners. The emollients were added to the
ethanol/water solution and heated to 65.degree. C. for 1 hour at
which point all waxes were melted. The "HYPAN QT-100" polymer was
gradually added while mixing at high speed with a high shear
rotor/stator mixer. This was mixed until well blended. To sample C,
the "SALCARE SC-92" was added, the contents shaken vigorously, and
once again sheared with the high shear mixer.
Wt % Emollient Trade Name A B C POLAWAX A31 1.5 1.5 1.5 GANEX V220
0.37 1 0.37 CERAPHYL 28 0.74 0.74 0.74 LANETTE 14 0.74 0.74 0.74
BERNEL Ester 2014 0.56 0.56 0.56 LIPOVOL MOS130 0.56 0.56 0.56
LEXOL PG865 0.56 0.56 0.56 HYPAN QT-100 1.0 1.0 0.75 SALCARE SC92
0.5
Sample A had a jelly/custard like consistency with a fairly long
dry time. After drying the product felt smooth. The "HYPAN" polymer
gave the product an objectionable odor which quickly fades. This
could probably be eliminated by proper clean up of the polymer.
Sample B had a thicker richer consistency than A with a soft feel.
Sample C had a nice consistency and was not jelly or custard-like.
Sample C was smooth, non-tacky, and not greasy.
Example 6
Compositions Containing Linear Synthetic Quaternary Polymers
A series of linear quaternary polymers was acquired from Nalco
Chemical Company, Naperville, Ill. and evaluated for use in
hydroalcoholic systems. Each polymer was supplied as an inverse
emulsion in a hydrocarbon oil (except for 2240 which was supplied
as an aqueous solution.) The polymers were added to the
hydroalcoholic solution at a concentration of 2% by weight. The
following table summarizes the polymer properties:
Trade Polymer.sup.2 Soluble in Soluble in Name Composition MW 50%
EtOH 68% EtOH Comments 7190 acrylamide >10 MM Y Y elastic,
stringy, modified cationic 7130 acrylamide >5 MM Y Y elastic,
stringy, modified cationic 7520 acrylamide >10 MM Y Y elastic,
stringy, modified cationic 7585 acrylic cationic 2.5 MM Y Y less
elastic, better consistency 2240 polymethacrylamidopropyl 50-100 K
Y Y very low viscosity trimethylammoniium chloride 92LT175
quaternized dimethylamino 1 MM Y N less elastic, good
consistency.sup.1 ethylacylate .sup.1. Composition had a slimy
feeling during application and during wash off. It was somewhat
sticky during dry down. .sup.2. Reported Molecular Weight -- MM
indicates 10.sup.6 and K indicates 10.sup.3 units in daltons.
The data appears to indicate that linear synthetic polymers
preferably have a molecular weight of less than 1 MM cps. Clearly
those polymers with a molecular weight of>5 MM form a
composition which is more elastic than desired. The data also
indicates that the percent charge alone does not determine the
solubility characteristics.
Example 7
Compositions Containing Gamma Exposed N-Vinyl Pyrrolidone
Copolymers
Polyvinylpyrrolidone (PVP) can be crosslinked by exposure to gamma
radiation. This can also be done using copolymers of NVP and at
least one other monomer. For use in this invention the copolymer
preferably includes a quaternary functionality. The two polymers
used are described below:
Trade Name Composition MW Manufacturer Luviquat 50:50 copolymer of
NVP and 800,000 BASF HM552 vinylimidazolium methochloride (CTFA
Polyquaternium 16) Gafquat copolymer of NVP and -- ISP HS-100
methacrylamidopropyltrimethyl- ammonium chloride (CTFA
Polyquaternium 28)
A portion of these polymers (which are supplied as 20% aqueous
solutions) were dried down into films at room temperature. The
films were broken up into approximately 0.5 square centimeters in
pieces sealed in glass jars and passed through a cobalt gamma
sterilization unit. The polymers were exposed two doses of
radiation at 42.2-44.7 Mrad and 15 Mrad of radiation, which was an
excessive level. After exposure to gamma radiation the dry polymer
was ground to a fine powder using a Warning blender. The data in
the table below shows the viscosities for compositions containing
2% by weight polymer. The polymer was added to the solvent (60:40
ethanol/water by weight) and heated to 70.degree. C. for 2 hours
and cooled overnight. Additional samples of the gamma irradiated
"LUVIQUAT HM552" were sheared with a high shear mixer. Sample e was
sheared after the polymer was heated and completely swollen.
Samples b, c, f-j, l-m were sheared immediately after addition of
the polymer to the ethanol/water solution followed by heating the
mixture to 72.degree. C. for 4 minutes. When cool, CHG was added to
a concentration of 0.5% by weight to the samples indicated in the
table below.
Sample Polymer Gamma (Mrad) Shear [polymer] % [CHG] % Viscosity
(cps) a Luviquat HM552 0 none 2 0 55 b Luviquat HM552 17 none 2 0
265 c Luviquat HM552 17 none 4 0 625 d Luviquat HM552 43 none 2 0
850-2200 e Luviquat HM552 43 shear 2 0 11,500 f Luviquat HM552 43
shear 2 0 8500 g Luviquat HM552 43 shear 2 0.5 870 h Luviquat HM552
43 shear 3 0.5 12,000 i Luviquat HM552 43 shear 4 0 60,000-80,000 j
Luviquat HM552 43 shear 4 0.5 25,000-30,000 k Gafquat HS-100 0 none
2 0 204 l Gafquat HS-100 17 shear 2 0 3000 m Gafquat HS-100 17
shear 3 0 8400 n Gafquat Hs-100 43 shear 2 0 160
This data indicates that for "LUVIQUAT HM552" (copolymer of NVP and
vinylimidazolium methochloride) the level of gamma irradiation
needs to be fairly high to ensure sufficient viscosity enhancement.
It appears that for Gafquat HS-100 exposure to gamma irradiation at
high levels (43 Mrad) may produce excessive crosslinking that
results in a decreased viscosity. For the "GAFQUAT HS-100" polymer,
17 Mrad may also be excessive. This experiment has not determined
the optimum exposure level.
Example 8
Associative Polymer
An associative polymer was prepared by reacting octadecylisocyanate
(Mondur O, Bayer Pittsburg, Pa.) with polyethylene imine (Polymin P
SG, BASF Corp. Mount Olive N.J.) and further neutralizing a
percentage of the residual amine groups. Specifically, to a
solution of Polymin P SG in ethanol/water was added Mondur O
through a 0.2 um syringe filter to remove any particulate. This was
allowed to react at room temperature for 60 min. After this time
concentrated HCl (37%) was used to neutralize a portion of the
residual amino groups on the polyethyleneimine. In order to achieve
a functional associative thickener, i.e. a polymer that will yield
a stable composition having a viscosity in excess of 4000 cps, the
proper level of hydrophobe substitution (reaction with Mondur O)
and neutralization with HCl was necessary. The table below
summarizes several formulations in terms of the level of reactants
used. All weights are in grams.
Polymin** Mondur O EtOH/ solvent Viscosity (g) (g) HCl (g) water
(g) (cps) 30.0 20.6 1.72 44.4 270 2000 30.0 20.6 pH 7.5* 44.4 270
158000 30 15.4 1.72 44.4 270 245000 30 15.4 3.44 44.4 270 <10,
unstable *HCl was added until the pH was adjusted to 7.5 **Polymin
SG is supplied as a 50% by weight solution in water.
Example 9
Quaternary Acrylate Polymer of Crosslinked Dimethylaminoethyl
Methacrylate
A quaternary acrylate polymer composed of colloidal particles of
lightly crosslinked dimethylaminoethyl methacrylate quaternized
using methyl chloride, is available from Allied Colloids Inc. as
Salcare SC95 and SC96. The base polymer, once cleaned by
precipitation from the carrier oils and residuals, can be
formulated to provide stable, viscous hydroalcoholic lotions. The
cleaning procedure is desirable to ensure maximum viscosity
enhancement as well as minimal odor.
The polymer was cleaned by placing 200 gm of Salcare SC95 into a
glass container and adding 200 gms of Toluene. The solution was
mixed and then approximately 2500 gm of Acetone was added with
additional mixing. A high shear mixer was placed into the container
to create a vortex. Slowly 125 gms of distilled water was added
into the vortex. A white polymer precipitated. After agglomeration,
the solvent phase was poured off. To the polymer dough was added
500 gm of distilled water, and 700 gms of acetone. Using the mixer
a uniform solution was created. Again using the mixer to create a
vortex 600 gms of acetone was added. The polymer again
agglomerated, and the liquid phase was poured off. To the polymer
dough was added 350 gms of distilled water and 700 gms of acetone.
The mixer was wed to create a uniform solution. Again using the
mixer to create a vortex 600 gms of acetone was added. The polymer
agglomerated, and the liquid phase was poured off. The doughy
polymer was placed in a polyethylene bag and squeezed to remove
additional solvent. The resulting polymer dough was dried in a
vacuum oven, overnight, at 30.degree. C. and at maximum vacuum.
Fully swollen "SALCARE 95" (DMAEMA Q) colloidal particles in
ethanol/water (68:32 weight ratio) have a particle size range from
1 to 25 microns. The mean particle size is 7 microns, as determined
by a Malvern Mastersizer E, utilizing light scattering.
The following compositions were prepared using the cleaned "SALCARE
SC95" (DMAEMA Q) according to the procedure above. The DMAEMA Q
polymer was first placed in the alcohol and water solution and
allowed to swell with occasional mixing. The emollients myristyl
alcohol, dimethicone, PG-15 Stearyl ether and CHG (if used) were
then added to the viscous solution with mixing until uniform.
Formulas A (0% CHG) 0.85 g DMAEMA Q polymer 0.25 g Myristyl
Alcohol, Lanette 14, Henkel 0.25 g Dimethicone, L45/350, Union
Carbide 0.25 g PPG-15 Stearyl Ether, Arlamol E, ICI 34.67 g 190
Proof Ethanols 13.78 g Distilled Water B (0.25% CHG) 1.30 g DMAEMA
Q polymer 0.25 g Myristyl Alcohol, Lanette 14, Henkel 0.25 g
Dimethicone, L45/350, Union Carbide 0.25 g PPG-15 Stearyl Ether,
Arlamol E, ICI 0.65 g Chlorhexidine Gluconate Solution, 20.48%
wt/vol 34.24 g 190 Proof Ethanol 13.06 g Distilled Water C (0.50%
CHG) 1.75 g DMAEMA Q polymer 0.25 g Myristyl Alcohol, Lanette 14,
Henkel 0.25 g Dimethicone, L45/350, Union Carbide 0.25 g PPG-15
Stearyl Ether, Arlamol E, ICI 1.30 g Chlorhexidine Gluconate
Solution, 20.48% wt/vol 33.79 g 190 Proof Ethanol 12.41 g Distilled
Water D (1.00% CHG) 1.75 g DMAEMA Q polymer 0.25 g Myristyl
Alcohol, Lanette 14, Henkel 0.25 g Dimethicone, L45/350, Union
Carbide 0.25 g PPG-15 Stearyl Ether, Arlamol E, ICI 2.60 g
Chlorhexidine Gluconate Solution, 20.48% wt/vol 33.69 g 190 Proof
Ethanol 11.26 g Distilled Water
Formulas A to C were gel-like lotions, formula D was a semi-viscous
solution. High salt concentrations tend to reduce the viscosifing
efficiency of DMAEMA Q at these high alcohol levels. Compositions
A-C were essentially gelled, translucent in appearance, with very
smooth cosmetic features. The formula had desirable dry time,
cosmetic feel, tack, emoliency and minimal smell.
These compositions were also checked for antimicrobial efficacy and
stability.
MIC Results (.mu.g/ml) Well Diffusion Centrifuge Stability Sample
#223 #502 % inactivation % Separation A 256-128 128 0 0 B 8 8 72 0
C 8 8 32 0 D 8 8-4 11 1
The MIC results indicate no inactivation of the CHG by the DMAEMA Q
thickener or the emollients. The centrifuge stability was
determined by centrifugation of the sample at 3,000 rpm for 30
minutes. The centrifuge was an American Scientific Products,
Labofuge B. The vials used to hold the sample were 16 mm
diameter--15 ml Polypropylene vials from Corning.
The following table shows the "SALCARE SC 95" viscosity profile
with and without CHG, cleaned and used as received and at varying
alcohol/water ratio. The formula are at 2.5% DMAEMA Q solids. Also
reported are conductivity results.
The conductivity was determined using a Model 76 Conductivity Meter
by Engineered Systems & Designs, Newark, Del. The temperature
of the sample was determined and the conductivity meter was
adjusted to this temperature. The electrode was immersed in the
sample, which was gently stirred. The range on the meter was
selected to give a reading of the solution. The electrode was
rinsed with deionized water between samples.
SC95 Aqueous % soln Cleaned CHG NaCl Ethanol % 50% DMAEMA 20% 190
Viscosity equivalent Formula by wt CHG solids Q Soln Ethanol DI
Water cps rpm .mu.mho (ppm) A 35% 0% 3.00 0.00 21.58 35.42 437,000
0.3 1010 515 B 45% 0% 3.00 0.00 27.75 29.25 437,000 0.3 780 394 C
55% 0% 3.00 0.00 33.91 23.09 437,000 0.3 550 274 D 65% 0% 3.00 0.00
40.08 16.92 356,000 0.3 430 211 E 75% 0% 3.00 0.00 46.25 10.75 *
0.3 110 44 F 85% 0% 3.00 0.00 52.41 4.59 * 0.3 50 13 G 90% 0% 3.00
0.00 55.50 1.50 * 0.3 50 13 H 35% 0% 1.50 0.00 22.15 36.35 468,000
0.3 750 379 I 45% 0% 1.50 0.00 28.48 30.02 468,000 0.3 620 311 J
55% 0% 1.50 0.00 34.81 23.69 468,000 0.3 440 217 K 65% 0% 1.50 0.00
41.13 17.37 468,000 0.3 330 159 L 75% 0% 1.50 0.00 47.46 11.04
412,000 0.3 240 112 M 85% 0% 1.50 0.00 53.79 4.71 * 0.3 10 0 N 90%
0% 1.50 0.00 56.96 1.54 * 0.3 10 0 O 35% 0.50% 3.00 1.58 21.47
33.95 293,000 0.3 1100 562 P 45% 0.50% 3.00 1.58 27.60 27.82
312,000 0.3 960 489 Q 55% 0.50% 3.00 1.58 33.74 21.69 183,000 0.3
720 363 R 60% 0.50% 3.00 1.58 36.80 18.62 60,000 0.3 600 300 S 65%
0.50% 3.00 1.58 39.87 15.55 300 50.0 540 269 T 75% 0.50% 3.00 1.58
46.00 9.42 * 0.3 250 117 U 85% 0.50% 3.00 1.58 52.14 3.28 * 0.3 230
107 V 90% 0.50% 3.00 1.58 55.20 0.22 * 0.3 170 75 W 35% 0.50% 1.50
1.58 22.04 34.89 406,000 0.3 810 410 X 45% 0.50% 1.50 1.58 28.33
28.59 306,000 0.3 770 389 Y 55% 0.50% 1.50 1.58 34.63 22.29 168,000
0.3 620 311 Z 60% 0.50% 1.50 1.58 37.78 19.15 119,000 0.3 520 258
AA 65% 0.50% 1.50 1.58 40.92 16.00 1,400 20.0 480 238 BB 75% 0.50%
1.50 1.58 47.22 9.70 * 0.3 240 112 CC 85% 0.50% 1.50 1.58 53.52
3.41 * 0.3 170 75 DD 90% 0.50% 1.50 1.58 56.66 0.26 * 0.3 150 65
*Viscosity below limits of viscometer. Salcare SC 95, Allied
Colloids, Inc. CHG Soln 20.1% w/v, Medichem S.A. Ethanol 190 Proof,
Aaper Alcohol DI Water, 3M DI tap Conductivity Meter Model 76 from
Engineered Systems & Designs, 119 Sandy Dr. Newark, DE 19713
The conductance of a body in mho is the reciprocal of the value of
its resistance in ohms.
Example 10
Modified Cellulosic Thickeners
The following formulation was prepared by first placing the Klucel
in the alcohol/water solvent and stirring occasionally until
uniform. Once uniform the emollients Cetyl alcohol and Phenyl
Trimethicone were added.
1.0 g Klucel HF 2.0 g Cetyl Alcohol 1.0 g Phenyl trimethicone, Dow
Corning 556 24.0 g deionized water 72.0 g IPA
The solution was a viscous clear solution which had a slippery feel
when wet. On drying the material had a tendency to ball up on the
palms during drying.
1.0 g Klucel HF 2.0 g Cetyl Alcohol 1.0 g Phenyl trimethicone, Dow
Corning 556 24.0 g deionized water 72.0 g Absolute Ethanol
The solution was a viscous opaque solution which had a slippery
feel when wet. On drying the material had a tendency to ball up on
the palms during drying.
While in accordance with the patent statutes, description of the
preferred weight fractions, processing conditions, and product
usages have been provided, the scope of the invention is not
intended to be limited thereto or thereby. Various modifications
and alterations of the present invention will be apparent to those
skilled in the art without departing from the scope and spirit of
the present invention. The Examples described in this application
are illustrative of the possibilities of varying the type, quantity
and ratio of composition as well as the methods for making
formulations of the present invention. All patents, patent
applications, and publications cited herein are incorporated by
reference in their entirety, as if individually incorporated.
* * * * *